Differential effects of ethanol on c-jun N-terminal kinase, 14-3-3 proteins, and Bax in postnatal day 4 and postnatal day 7 rat cerebellum.
Differential effects of ethanol on c-jun N-terminal kinase, 14-3-3 proteins, and Bax in postnatal day 4 and postnatal day 7 rat cerebellum.
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DOI：
10.1016/j.brainres.2011.11.010
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发表时间：
2012-01-13
期刊：
影响因子：
2.9
通讯作者：
Posados M
中科院分区：
文献类型：
--
作者：
Heaton MB;Paiva M;Kubovic S;Kotler A;Rogozinski J;Swanson E;Madorsky V;Posados M
这些研究比较了酒精敏感高峰期(出生后第4天[P4])和相对耐受高峰期(P7)的新生大鼠小脑中乙醇对上游细胞成分和促进Bax相关细胞凋亡的相互作用的影响。分析促凋亡的c-jun N末端激酶(JNK)、Bax和14-3-3锚定蛋白的基础水平，以及这些物质在P4和P7对乙醇的反应性。在乙醇处理后的两个年龄段，还研究了Bax与14-3-3的二聚化，这一过程将Bax隔离在细胞质中，从而抑制其线粒体易位和线粒体膜电位的破坏。用培养的小脑颗粒细胞检测JNK对乙醇诱导的细胞死亡的保护作用。基础水平的JNK在P4时显著高于P7，但在其他蛋白中没有发现差异。酒精暴露后，P4组JNK活性增加，胞浆Bax和线粒体易位Bax增加，而保护性14-3-3蛋白仅在P7组增加。乙醇处理导致Bax：14-3-3杂二聚体在P4时减少，但在P7时不减少。体外抑制JNK活性对乙醇神经毒性有部分保护作用。因此，这一中枢神经系统区域对乙醇的不同时间脆弱性与凋亡相关物质(如JNK)水平的不同以及细胞反应的不同有关，有利于最敏感年龄的细胞凋亡和耐药年龄的存活。造成这一脆弱性的上游因素可以成为未来治疗策略的目标。
These studies investigated ethanol effects on upstream cellular elements and interactions which contribute to Bax-related apoptosis in neonatal rat cerebellum at ages of peak ethanol sensitivity (postnatal day 4 [P4]), compared to later ages of relative resistance (P7). Analyses were made of basal levels of the pro-apoptotic c-jun N-termimal kinase (JNK), Bax, and the 14-3-3 anchoring proteins, as well as the responsiveness of these substances to ethanol at P4 versus P7. Dimerization of Bax with 14-3-3 was also investigated at the two ages following ethanol treatment, a process which sequesters Bax in the cytosol, thus inhibiting its mitochondrial translocation and disruption of the mitochondrial membrane potential. Cultured cerebellar granule cells were used to examine the protective potential of JNK inhibition on ethanol-mediated cell death. Basal levels of JNK were significantly higher at P4 than P7, but no differences in the other proteins were found. Activated JNK, and cytosolic and mitochondrially-translocated Bax were increased in P4 but not P7 animals following ethanol exposure, while protective 14-3-3 proteins were increased only at P7. Ethanol treatment resulted in decreases in Bax:14-3-3 heterodimers at P4, but not at P7. Inhibition of JNK activity in vitro provided partial protection against ethanol neurotoxicity. Thus, differential temporal vulnerability to ethanol in this CNS region correlates with differences in both levels of apoptosis-related substances (e.g., JNK), and differential cellular responsiveness, favoring apoptosis at the most sensitive age and survival at the resistant age. The upstream elements contributing to this vulnerability can be targets for future therapeutic strategies.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
DOI：
10.1016/0165-3806(86)90208-7
发表时间：
1986-03-01
期刊：
DEVELOPMENTAL BRAIN RESEARCH
影响因子：
--
作者：
MANTHORPE, M;FAGNANI, R;VARON, S
通讯作者：
VARON, S
DOI：
10.1097/00000374-199706000-00028
发表时间：
1997-06-01
影响因子：
3.2
作者：
Goodlett, CR;Eilers, AT
通讯作者：
Eilers, AT
影响因子：
16.2
作者：
ANKARCRONA, M;DYPBUKT, JM;NICOTERA, P
通讯作者：
NICOTERA, P
DOI：
10.1016/j.molbrainres.2004.06.034
发表时间：
2004-10-22
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Ge, Y;Belcher, SA;Light, KE
通讯作者：
Light, KE